This invention relates to methods of reducing cardiac damage, particularly cardiac damage as a result of chemotherapy or radiation therapy. The invention also relates to the treatment of autoimmune diseases, fibrosis, inflammatory diseases, organ transplantation, and conditions associated with oxidative stress.
Right ventricular (RV) failure is a major determinant of morbidity and mortality for millions of individuals worldwide who suffer from lung disease or heart failure (McLaughlin et al., J Am Coll Cardiol. 53:1573-1619, 2009, Haddad et al., Circ Heart Fail. 4:692-699, 2011). RV failure is commonly a direct consequence of RV pressure overload (RVPO). Recent data confirms that elevated pulmonary artery systolic pressures are inversely associated with RV ejection fraction and directly related to increased mortality in both lung disease and left heart failure (Benza et al., Circulation. 122:164-172, 2010, Bursi et al. J Am Coll Cardiol. 59:222-231, 2012).
TGFβ1 is a powerful cytokine that governs cardiac fibrosis and signals through a heteromeric receptor complex comprised of a Type II ligand-binding receptor, a Type I activin-like kinase signaling receptors, and Type III accessory receptors, including endoglin. Upon activation, this receptor complex phosphorylates downstream effector proteins known as Smads (canonical pathway) or mitogen activated protein kinases (noncanonical pathway), including extracellular regulated kinase (ERK) (Leask, Cardiovasc Res. 74:207-212, 2007, Massague, Annu Rev Biochem. 67:753-791, 1998). Specifically, TGFβ1-induced phosphorylation of Smads-2/3 and ERK promotes Type I collagen synthesis and fibroblast proliferation (Kuwahara et al., Circulation. 106:130-135, 2002).
The calcium-dependent serine/threonine phosphatase, calcineurin, is another critical mediator of maladaptive cardiac remodeling, defined by excessive fibrosis and hypertrophy. Studies have shown that calcineurin increases expression of the canonical transient receptor protein channel 6 (TRPC-6), which triggers calcium influx and subsequent calcineurin activation, thereby setting up a self-propagating mechanism for pathologic hypertrophy, fibrosis, and increased mortality in heart failure. Noncanonical TGFβ1 signaling through TRPC-6 was reported to be an important stimulus for calcineurin-mediated alpha-smooth muscle cell active (α-SMA) expression, a marker of myofibroblast transformation and a critical component of cardiac fibrosis.
While it was recently reported that reduced endoglin expression limits left ventricular (LV) fibrosis and improves survival in a murine model of LV failure (Kapur et al., Circulation. 125:2728-2738, 2012), less is known about the functional role for endoglin in the RV and generally in organ fibrosis. Accordingly, there is a need to develop new targets for promoting RV cardiac remodeling for the treatment of heart failure. There is also a need to develop new targets for reducing organ fibrosis, such as, lung disease, and kidney disease, as well as new therapeutic approaches to prevent organ, heart, and other fibrosis related morbidity and mortality.